Mechanisms of Desmosome Regulation and Disassembly in the Skin Disease Pemphigus

Project: Research project

Project Details

Description

Pemphigus is a class of devastating epidermal blistering diseases in which autoantibodies are generated
against cell-cell adhesion molecules present in the skin and mucous membranes. Pemhigus IgG target
desmosomes, a structure that couples the keratin intermediate filament network to regions of strong cell-cell
adhesion. In pemphigus vulgaris (PV), the primary target of the autoantibodies is desmoglein-3 (Dsg3), a
member of the desmosomal cadherin subfamily of adhesion molecules. The work outlined in this proposal
investigates the mechanisms by which IgG from pemphigus vulgaris patients disrupts cell-cell adhesion. It is
hypothesized that PV IgG disrupt desmosomes by causing Dsg3 internalization from the cell surface, leading
to desmosome destabilization and loss of keratinocyte adhesion. This hypothesis will be tested using a
series of in vitro cell culture models that employ cellular and molecular approaches to define the
mechanisms by which PV IgG cause Dsg3 internalization and desmosome disassembly. These studies will
reveal the cellular machinery and pathways that mediate Dsg3 endocytosis, and how cytoplasmic
components of the desmosome regulate Dsg3 internalization. These studies will be complemented by in
vivo models of disease to determine if agents that block PV IgG induced loss of adhesion in vitro can also
block loss of adhesion in vivo. A panel of antibody reagents will be employed, including PV patient IgG,
human monoclonal antibodies isolated from patients, and mouse monoclonal Dsg3 antibodies with varying
degrees of pathogenic activity. These reagents will be used to reveal relationships between desmosome
disassembly pathways and antibody pathogenicity profiles to determine how pemphigus IgG cause disease
at the cellular level. These studies are designed to generate new insights into the basic cellular mechanisms
that regulate cell-cell adhesion, and to expose new therapeutic targets for the treatment of pemphigus and
other skin diseases characterized by epidermal fragility.
StatusFinished
Effective start/end date8/15/077/31/08

Funding

  • National Institute of Arthritis and Musculoskeletal and Skin Diseases: $382,500.00

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